Glycosides lect 5 and 6 - AL-Mustansiriyah University08_54_28... · sugar moiety of a glycoside can...

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Page 1: Glycosides lect 5 and 6 - AL-Mustansiriyah University08_54_28... · sugar moiety of a glycoside can be ... Glycosides that have soap ... on heart muscle. α- β unsaturated latone

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Glycosides Glycosides are compounds that yield one or more sugars upon hydrolysis. The term

glycoside is a generic term for natural product that is chemically bound to a sugar.

Thus the glycoside composes of two parts: the sugar and the aglycone. The aglycon

may be a terpene , a flavonoid, a coumarine or any other natural product. Glycoside

showed extra chemical diversity. Among the sugars found in natural glycosides, D-

glucose is the most abundant one, L rhamnose and L-fructose also occur quite

ferequently. Of the pentoses : L-arabinose is more common than D-xylose. The sugar

part can be disaccharide.

Because of the cyclic structure of the sugar, two diastereoisomers of the glycoside

exist depending on the configuration of the anomeric carbon. These diastereoisomers

are called anomers and are designated as α and β. This classification depends on the

glycosidic linkage (above the linkage is β), below the linkage is α.

Chemically, glycosides are usually mixed acetals in which the hydroxyl group on the

anomeric carbon is replaced by a moiety possessing a nucleophilic atom. Thus the

sugar moiety of a glycoside can be joined to the aglycone via

- Oxygen atom (O-glycosides -1)

- Carbon atom (C-glycosides -2)

- Nitrogen atom (N-glycosides- 3

- Sulfur atom (S-glycosides-4)

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Nomenclature of glycosides

In the nomenclature of glycosides the trivial names have an “in” ending, and the

names indicate the source of glycoside, for example, digitoxin from Digitalis, salicin

from Salix, and prunasin from Prunus. The systematic names are usually formed by

replacing the “ose” suffix of the parent sugar with “oside”. The anomeric prefix (α- or

β-) and the configurationally prefix (D or L) immediately precede the sugar stem

name, and the chemical name of the aglycone precedes the name of the sugar. For

example the name of salicin is o-hydroxy-methylphenyl β-D-glycopyranoside.

o-hydroxy-methylphenyl β-D-glycopyranoside

Classification of glycosides

The classification of glycosides is a difficult matter. If the classification is based on

the sugar group, a number of rare sugars are involved; for example glucosides and

rhamnosides, if the aglycone group is used as a basis of classification , all class of

natural product will involved Example lignan glycosides, alkaloidal glycosides etc.

A therapeutic classification, although excellent from a pharmaceutical

viewpoint, omits many glycosides of pharmacognostic interst.example

cardiac glycosides.

Based on properties or function.

Glycosides that have soap like properties are called saponin. Similarly, glycosides that

liberate hydrocyanic acid (HCN) on hydrolysis are known as cyanogenic glycosides.

Acorrdingly the types of glycosides are

Cardiac glycosides

Cyanogenic glycosides

Phenolic glycosides (flavonoids, lignans and other phenolic compounds)

Aldehyde glycosides

Anthraquinone glycosides

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Saponine glycosides [terpene (triterpenoid) and sterol unit]

Hydrolysis of glycosides

All natural glycosides are hydrolyzed into a sugar and another organic compound by

boiling with mineral acids; but differ in the in the ease with which this hydrolysis is

performed.

Enzymatic hydrolysis is more specific. Many of the enzymes hydrolyzed only a single

glycoside; however two enzymes, namely emulsin of almond and myrosinase of

black mustard seeds, each hydrolyze a considerable number of glycosides. Rhamnase

is the enzymes that hydrolyze rhamnoside glycosides.

Biosynthesis of glycosides

The biosynthetic pathways are widely variable depending on the type of aglycone as

well as the glycone units. The aglycone and the sugar parts are biosynthesized

separately, and then coupled to form a glycoside. The coupling of the two parts occurs

via phosphorylation of a sugar to yields a sugar 1- phosphate which reacts with a

uridine (uracil nucleo base and ribose) triphosphate to form a uridine diphosphate

sugar (UDP-sugar) and inorganic phosphate. This UDP sugar reacts with the aglycone

to form the glycoside and a free UDP

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Cyanogenic glycosides

Cyanogenic glycosides names come from (yield HCN on hydrolysis)

Biosynthesis of these glycosides begin with L-phenylalanine

Amygdalin found in almond (prunus amygdalus) Fam: Rosaceae. Linseed (linum

sativum) Fam: Linaceae contain the glycoside linamarin.

HCN liberated on hydrolysis can be determined by a simple color test using sodium

picrate (yellow) which turns red in contact with HCN.

Uses and side effects

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The extracts of plants that contain the cyanogenic glycoside are used as flavoring

agents in many pharmaceutical preparations. Amygdalin has been used for treatment

for cancer and as cough suppressant.

Excessive ingestion of this glycoside can be fatal. Some foodstuffs containing

cyanogenic glycosides can cause severe gastric irritation and damage if not properly

handled.

Anthraquinone glycosides

These glycosides are anthracene derivatives most of them contain anthraquinone

skeleton such as cascara sagrada, frangula, aloe, rhubarb and senna.

These drugs are used as cathartics. The glycosides, upon hydrolysis, yield aglycones

that are di-, tri-, or tetrahydroxyanthraquinones or modifications of these compounds.

Atypical example is frangulin A, which hydrolyses to form emodin (1,6,8-trihydroxy-

3-methylanthraquinone) and rhamnose. The structural relationships of emodin are

shown in the following figure.

O

H H

OH

HO

OH

Me

oxidation

O

H OH

OH

HO

OH

Me

emodin anthrone emodine oxanthrone

oxidation

OOH

HO

OH

Me

emodin

O

OHOH

HO

OH

Me

emodin anthranol

oxidationOOH

HO

OH

Me

O OH

OH

OH

Me

emodin dianthrone

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Glycosides of anthranols, dianthrones, and oxanthrones have significant therapeutic

action. They employed as cathartic which exert their action by increasing the tone of

the smooth muscle in the wall of the colon and stimulate the secretion of water and

electrolytes into the large intestine (bulk laxatives).Glycosides of anthranols and

anthrone (Aloe and Rhubarb) elicit a more drastic action than other anthraquinone

leading to discomforting gripping action. The drug of choice is cascara and senna.

Aloe is used for treatment of minor burns. The action is due to presences of aloin A

and Aloin B. Action of senna due to presence of the glycosides (sinnoside A and B).

Biosynthesis of anthraquinone glycosides

Feeding of labeled acetate to organisms produce anthraquinone glycosides have

revealed that the distribution of radioactivy in these compounds is consistent with

formation via a head to tail condensation of acetate units. Anthranols and anthrone are

likely to be intermediates in the formation of anthraquinone compounds.

Test for anthraquinone glycosides

Powdered plant material is mixed with organic solvent and filtered. Aqueous base

(NaOH or NH4OH) is added to it. A pink or violet color in the base layer indicates the

presence of anthraquinone nucleus. This test is specific for aglycone, therefore

hydrolysis with HCl in case of O-glycosides and ferric chloride/HCl for C-glycosides

must be performed.

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Isoprenoids glycosides

The aglycone of this type of glycosides is biosynthetically derived from isoprene

units. There are two types of isoprenoid glycosides: saponins and cardiac glycosides

Saponine glycosides

Saponins form colloidal solutions in water that foam upon shaking. They have a bitter

acrid taste and have irritation action to mucous membrane. They destroyed red blood

corpuscles by hemolysis and are toxic. Upon hydrolysis they yield an aglycone known

as a sapogenin which can be one of two possible chemical classes either steroid

(cyclopentaphenanthrene) or triterpenoid (pentacyclic structures)

The two major types of steroidal sapogenin are diosgenin and hecogenin. Sapogenin

are used in the commercial production of sex hormones for clinical use, for example,

progesterone’s derived from diosgenin (from the plant Dioscorea from Mexico)

Other steroidal hormone like cortisone can be prepared from hecogenin which can be

isolated from Sisal leaves found extensively in East Africa.

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HO

H

H

H

Hecogenin

O

In triterpenoid saponins, the aglycone is a triterpene

which is found in ginseng roots (tonic) and l

used as expectorants and flavoring for gum.

Cardiac glycosides Glycosides that exert a prominent effect on heart muscle

cardiac glycosides example digitoxin from Digitalis purpurea. Their

specifically on myocardial contraction

Convallaria, Nerium and

is sometimes referred to as a

alkene and olide (cyclic ester).

found in the plant Nerium oleander in Arabic

O

H

H

H

Cortisone

O

OO

In triterpenoid saponins, the aglycone is a triterpene C-30, for example ginsenosides

in ginseng roots (tonic) and liquorices contains glycyrrhetic

ectorants and flavoring for gum.

Glycosides that exert a prominent effect on heart muscle and heart rhythm

cardiac glycosides example digitoxin from Digitalis purpurea. Their

specifically on myocardial contraction. They are commonly found in the genera

and Digitalis. The aglycone portion is steroidal in nature and it

sometimes referred to as a cardenolide being cardioactive and possessing an

(cyclic ester).

Digitoxin and digoxin

Oleadrin (toxic cardiac glycoside

found in the plant Nerium oleander in Arabic ا�����

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O

H

OHOH

, for example ginsenosides

contains glycyrrhetic acid is

and heart rhythm are called

cardiac glycosides example digitoxin from Digitalis purpurea. Their effect is

They are commonly found in the genera

The aglycone portion is steroidal in nature and it

ioactive and possessing an

Oleadrin (toxic cardiac glycoside

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The most widely studied plant that contains these compounds is the foxglove

(Digitalis purpurea) of the family Scrophulariaceae which is used from 18 century for

the treatment of heart disease. The plant contains the medicinal agent's digoxin (which

is more widely used) and digitoxin. Digoxin is also found in Digitalis lanata.

Digitoxin yields one molecule of digitoxigenin and three of digitoxose. Digitoxin is

insoluble in water and slightly soluble in alcohol. It is the most lipid soluble drug used

in cardiac diseases.

Related glycosides which because they are very fast acting compounds are used in

emergencies via IV routs are lanatoside C and diacetyl-lanatoside C.

Bufanolides (derived their name from the generic name of toad that produce bufalin)

in which the lactone (cyclic ester) contains 6 member ring is less abundant in nature,

for example proscillardin A, found in the plant squill ( Scilla maritima). This glycoside

is used as rodenticide due to sever toxicity

SAR An unusual aspect of chemistry of both cardenolides and bufadienolide is that is the

CD ring junction has the cis –configuration.

Both sugar and aglycone parts are responsible for activity. The sugar probably

enhances the binding to heart muscle and the aglycone moiety has the desired effect

on heart muscle. α- β unsaturated latone ring that is attached on the 17 position of the

steroid nucleus is responsible for activity. Reduction of the double bond in the lactone

ring results in inactive compound. For activity that is more prominent 3-OH should be

on β- position. Oxygen substitution on the steroid nucleus influences the distribution

and metabolism of the glycosides. In general the more hydroxyl groups in the

molecule the more rapid the onset of action.

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Drug interaction Digoxin interacts with cation levels. Potassium depletion increase the susceptibility to

cardiac glycoside toxicity, therefore patient on thiazide diuretics which cause

potassium depletion should decrease the dose of digoxine or received a potassium

therapy. Conversely high calcium level enhances the activity of digoxin, therefore,

ingestion of high amount of milk or calcium gluconate should be avoided in patient on

digoxin therapy.

Mechanism of action

The mechanism of action of the cardiac glycosides is still not completely known;

however, observation has implicated Na+, K+ -ATPase as the receptor enzyme. This

enzyme catalysis the active transport of Na+ out of the cell and subsequent transport

of K+ into the cell. In myocardium the ion exchange is rapid because it is required

after each heart beat; therefore an inhibition of ATPase has a great effect on heart

tissues.

Page 116 in your text book for more details.

Biosynthesis of cardiac glycosides

The steroid nucleus is biosynthesized via acetate mevalonate pathway (polyketide). If

we look to the side chain of cortisone we may suggest that the hydroxyl may oxidize

to acid then lactonozation occurs.

Physical and chemical properties

The glycosides are fairly soluble in water and slightly soluble in ethanol and

chloroform: digitoxin is far more soluble in chloroform than digoxin, which is fairly

soluble in dilute ethanol and in ethanol-chloroform mixtures. Both are sparingly

soluble in ethyl acetate. Cardiac glycosides containing 3 or 4 monosaccharides are

soluble in water. Aglycones of cardiac glycosides are soluble in organic solvents and

practically insoluble in water. Cardiac glycosides easily hydrolyze. Upon hydrolysis,

they yield the sugars and aglycone. Primary glycosides such as lanatoside C are

water-soluble, soluble in dioxane, sparingly soluble in chloroform (1 g in 2 L), and

virtually insoluble in methanol. The presence of the lactone renders the molecule

labile, and likely to open in an alkaline medium.

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Other cardioactive drugs

Oleander: The leaves of Nerium oleander, Fam; Apocyanaceae have been used to

treat cardiac diseases. Oleandrin is a derivative of digoxin.

Strophanthus: Is the dried ripe seeds of strophanthus kombe, Fam; Apocyanaceae. K

strophanthoside, also known as stroposide is the principle glycoside in the plant that

has been used in Africa as arrow poisoning, when sent to Europe the effect on heart

muscle was noticed.

Isothiocyanate glycosides (glucosinolates) A group of glycosides which upon hydrolysis by the enzyme myrosinase yield a

glucose and aglycon which undergo spontaneous rearrangement with the loss of

sulphate to give an isothiocyanate as the major product. In this type of glycoside the

sulphur atom is bonded to sugar (S-glycoside) and the second sulfur present in

sulfonated oxime group (C=NOH)

Glucosinolates have a limited distribution in the plant families and are characteristic

constituent of the mustard family (Brassicaceae), including rape seed, mustard, turnip,

broccoli and cabbage. Mustard family vegetables have been found to have

anticarcinogenic properties. For example indole-3 carbinol derived from indomethyl-

glucosinolate which is widely distributed in mustard family has been shown to reduce

risk of estradiol-linked cancer. Broccoli found to contain enzymes that have a

protection against cancer (prevention).

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Biosynthesis of glucosinolates

Biosynthetic pathway involves N

yield an aldoxime intermediate. The aglycones may be aliphatic

aromatic (white mustard) derived from amino acid

Sulphur-35 from labelled sulphate, sulphide, thiosulphate and methionine was

incorporated into sinigrin iso

more readily incorporated than was that from sulphide, thiosulphate or methionine.

When inorganic sulphur-35 was supplied, about 80 per cent of the radioactivity of

sinigrin was in the bisulphate moiety

with methionine-35S as the tracer the

the radioactivity. The data suggest that methionine sulphur is incorporated into

sinigrin by a different pathway than are the various forms of inorganic sulphur.

NH2

S

O

OH

methionine

*

Uses

Black mustard is a local irritant and an emetic. Externally

Commercially it is used as condiment.

Other organosulfur drugs

Garlic

Consist of the bulb of Allium sativum

medicine from the time of Pharaohs. The intact cells of garlic contain the odorless

sulfur containing amino acid derivative (+)

When the cell is crushed it comes into contact with the enzyme alli

convert it to allicin (bad smell, diallyl

antibacterial activity. Garlic also posse's antihyperlipedemic and

aggregation.

Biosynthesis of glucosinolates

Biosynthetic pathway involves N-hydroxylation and oxidative decarb

yield an aldoxime intermediate. The aglycones may be aliphatic (in black mustard)

derived from amino acid.

35 from labelled sulphate, sulphide, thiosulphate and methionine was

incorporated into sinigrin isolated from mature horse-radish leaves. Sulphate

more readily incorporated than was that from sulphide, thiosulphate or methionine.

35 was supplied, about 80 per cent of the radioactivity of

sinigrin was in the bisulphate moiety and 20 per cent in the isothiocyanate

S as the tracer the isothiocyanate portion contained 90 per cent of

the radioactivity. The data suggest that methionine sulphur is incorporated into

by a different pathway than are the various forms of inorganic sulphur.

Black mustard is a local irritant and an emetic. Externally the drug

Commercially it is used as condiment.

organosulfur drugs

Allium sativum Fam; Lilicaeae. The plant was used as food and

medicine from the time of Pharaohs. The intact cells of garlic contain the odorless

sulfur containing amino acid derivative (+)-S-allyl-L- cysteine sulfoxide.(alliin).

crushed it comes into contact with the enzyme alli

bad smell, diallyl thiosulfinate). Allicin has a powerful

antibacterial activity. Garlic also posse's antihyperlipedemic and inhibit platelets

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hydroxylation and oxidative decarboxylation to

(in black mustard) or

35 from labelled sulphate, sulphide, thiosulphate and methionine was

radish leaves. Sulphate-S was

more readily incorporated than was that from sulphide, thiosulphate or methionine.

35 was supplied, about 80 per cent of the radioactivity of

isothiocyanate. However,

portion contained 90 per cent of

the radioactivity. The data suggest that methionine sulphur is incorporated into

by a different pathway than are the various forms of inorganic sulphur.

the drug is rubefacient.

Fam; Lilicaeae. The plant was used as food and

medicine from the time of Pharaohs. The intact cells of garlic contain the odorless

cysteine sulfoxide.(alliin).

crushed it comes into contact with the enzyme alliinase which

thiosulfinate). Allicin has a powerful

inhibit platelets

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H2CHCS

COOIH

NH2O

H2C

CHH2C

Alliin

alliinase SH

O

+ NH3H3C COOH

O

+

2 moles,spontanteously

H2CSS

O H2C CH2 + H2O

Pyruvic acid

Measurement of the total activity of garlic is determined by the amount of bioactive

allicin produced; therefore commercial garlic preparations have a great variation in

their ability to produce allicin because the mode of preparation greatly influences the

stability of alliin and alliinase. Enteric coated tablets or capsules have enhanced

activity because stomach acid inactivates allinase.

Alcohol glycosides Salicin Is a glycoside obtained from Salix purpurea and Salix fragilis. Emulsin is the enzyme

responsible for the hydrolysis of salicin to salicyl alcohol and glucose. It s action is

similar to salicylic acid; probably it oxidized in the body to this acid. The glycoside

populin (benzoylsalicin) is also found in with salicin in the barks of Salicaceae.

Recognition of the properties of salicin clarifies many folkloric uses of poplar and

willow barks.

Phenolic glycosides

Phenolic compounds are C-6-C3 metabolites derived from shikimic acid.

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Figure showing the relation between phenypropanoid metabolites